Migraine is one of the most common diseases. About 10% of the population suffer from it (Worthington, 1996, Current migraine theory, Can. J. Clin. Pharm., 3, 39-51). This makes it one of the genuinely endemic diseases.
The distinguishing characteristic of classical migraine is an early stage accompanied by impaired vision, the so-called visual aura (K. Kranda, J. J. Kulikowski, 1984, Visual Aura in classical migraine, in: Neurobiology of Pain, eds. Holden & Wilmslow, MUP) that can last just minutes or for several hours. Unilateral or bilateral pulsating pain may follow the visual aura. Occurrence of the visual aura is only reported by about 20% of people suffering from migraine and defines the so-called “classical migraine” (M. L. Leone et al., 1995, A review of the treatment of primary headaches, Ital. J. Neurol. Sci., 16, pp. 577-586). The visual aura is not always followed by headache, and some patients may have pain attacks with or without the visual aura in different incidents (W. F. Stewart et al., 1992, Prevalence of migraine headache in the United States, J.A.M.A., 267, pp. 64-69); J. Olesen et al., 1994, Migraine classification and diagnosis, Neurol., 44, pp. 56-510).
Summarizing, the classical migraine consists of two main phases: a) the aural phase that may not always occur, and b) the acute, painful phase characterized by headache. This latter headache phase is characterized by throbbing pain and nausea. It is frequently accompanied by photophobia or sensitivity to noise and can last for days (P. J. Goadsby, 1997, Current concepts of the pathophysiology of migraine, Neurol. Clin., 15, pp. 27-42).
The causes and mechanisms of migraine have not been fully understood. Depression spreading in the cerebral cortex has been proposed as the initiator of the visual aura of classical migraine (Lauritzen, 1994, Brain, 117, pp. 199-210). However, theoretical considerations of the cytoarchitecture of the visual cortex make this hypothesis seem not very likely (K. Kranda, J. J. Kulikowski, 1984, Visual Aura in classical migraine, in: Neurobiology of Pain, Eds. Holden & Wilmslow, MUP).
Numerous pharmaceuticals have been proposed or are already in use for the treatment and prevention of migraine. These include analgesics, antihistamines, calcium channel blockers, and the group of serotonin agonists/antagonists such as ergot alkaloids, sumatriptan, pizotifene, and propanolol. Other pharmacological classes can potentially be used for migraine treatment and prevention such as vasodilators, neuroleptics, β-receptor blockers, and antiepileptics such as sodium valproate.
Although considerable progress has been made in migraine treatment in recent years such as using sumatriptan, a 5-HT1 agonist, patients having this disease are often misdiagnosed and inappropriately treated (Worthington, 1996, Can. J. Clin. Pharm., 3, pp. 39-51). None of the available treatments causes permanent relief from migraine-type headache. For example, the disease reoccurs within a period of 24 hours in 40% of the patients that were given sumatriptan. All substances used in treatment as yet are not very specific to serotonin receptors, which causes side effects (such as coronary constriction).
5-HT2B antagonists are said to have great potential for the prevention and treatment of migraine. It has been observed that 5-HT2B agonists such as m-chlorophenyl piperazine, can cause migraine attacks in sensitive individuals (Fozard and Gray, 1989, Trends Pharmacol. Sci, 10(8), pp. 307-309). Inversely, HT2Bantagonists can prevent a migraine outbreak (Kalkman, 1994, Life Sci., 54, pp. 641-644).
The most effective pharmaceuticals as yet in migraine prevention, methysergide, pizotifene, and propanolol, have an antagonistic effect on 5-HT2B-Rezeptoren (Kalkman, 1994, Life Sci., 54(10), pp. 641-644). Methylergometrine as the main active metabolite of methysergide in humans also has a strong antagonistic effect on 5-HT2B receptors (Fozard and Kalkman, 1994, Arch. Pharmakol. 350(3), pp. 225-229).
5-HT2B receptors were localized in endothelial cells (intima) including the endothelial cells of blood vessels in the brain (Ullmer et. al, 1995, FEBS-Lett., 370(3), pp. 215-221) and trigger vessel relaxation by releasing nitric oxide (NO). NO may also have a part in causing migraine (Olesen et al., 1994, Ann. Neurol., 28, pp. 791-798). All migraine agents mentioned above have considerable side effects.
Another desired characteristic for an anti-migraine effect is the strong efficacy of the substances described on thrombocytes as various disorders of the thrombocyte function are known to occur with migraine. These manifest themselves by increased adhesion and aggregation during a fit, in sludging and the resulting microcirculation as well as the release of serotonin, thromboxane A and other vasoactive substances (see the overview in S. Diamond, Migraine Prevention and Management, Marcel Dekker, Basel, 1990). The effects on thrombocytes are desired whenever thrombocyte aggregation is disturbed or increased, independent of migraine.